2926 J . Org. Chem., Vol. 64, No. 8, 1999
Notes
Boc-Nrh Ile-a za Gly-OBn (4b): yield 80%; mp 110 °C; IR
blocks can be integrated in peptidic fragments or com-
bined with other amino acids’ analogues, increasing the
diversity of peptidomimetics.
1
(KBr) 3250, 1750, 1712, 1681 cm-1; H NMR (CDCl3) δ 0.90 (t,
3H, J ) 7.2 Hz), 0.95 (d, 3H, J ) 6.5 Hz), 1.20 (m, 2H), 1.40 (s,
9H), 2.70 (m, 1H), 3.40 (s, 2H), 5.10 (s, 2H), 5.85 (s br, 1H), 6.35
(s br, 1H), 7.30 (m, 5H), 10.00 (s br, 1H); HR-MS FAB m/z for
C
19H30N4O5 calcd 497.2012 (M + H+), obsd 497.2020. Anal.
Exp er im en ta l Section
Calcd: C, 57.87; H, 7.61; N, 14.21. Found: C, 58.10; H, 7.79; N,
14.40.
NMR spectra were run at 200, 300 (1H), or 75.5 MHz (13C).
HR-MS were obtained from the Centre Re´gional de Mesures
Physiques de l’Ouest, using an MS/MS mass spectrometer ZAB
Spec TOF. Infrared spectra were recorded on an FT-IR spec-
trometer as suspensions in KBr. Elemental analyses were
performed by the analytical laboratory, CNRS (Lyon).
Boc- or Z-protected alkyl or aralkyl hydrazines 2b and 2c were
prepared according to literature procedures by reduction of Boc-
or Z-protected hydrazones, derived from the reaction of Boc- or
Z-carbazate with either aldehyde or ketone.9,11 Carbomethox-
ylation of 2a with MocCl and deprotection by HCl afforded 2b.
Step A. To a stirred and cooled (0 °C) solution of N-protected
hydrazine (30 mmol, 3 equiv) in methylene chloride (20 mL) and
pyridine (30 mmol, 3 equiv) was added the bromo acetyl bromide
(10 mmol, 1 equiv) in methylene chloride (5 mL). The reaction
mixture was stirred over a period of 6 h and washed three times
with water (50 mL). The organic phase was dried over Na2SO4.
The solvent was removed under reduced pressure, and the crude
product slowly precipitated.
Boc-Nrh Leu -a za Gly-OBn (4c): yield 54%; mp 128 °C; IR
(KBr) 3250-3100, 1732, 1600 cm-1; 1H NMR (CDCl3) δ 0.97 (d,
6H, J ) 6.4 Hz), 1.43 (s, 9H), 1.68 (m, 1H), 2.53 (d, 2H, J ) 6.9
Hz), 3.49 (s, 2H), 5.16 (s, 2H), 5.54 (s br, 1H), 6.49 (s br, 1H),
7.35 (m, 5H), 9.84 (s br, 1H); HR-MS FAB m/z for C19H30N4O5
calcd 395.2294 (M + H+), obsd 395.2295. Anal. Calcd: C, 57.87;
H, 7.61; N, 14.21. Found: C, 58.17; H, 7.61; N, 14.14.
H-Nrh P h e-a za Gly-OtBu (4d ): yield 75%; mp 140 °C; IR
(KBr) 3291, 3191, 3152, 1732, 1690, 1619 cm-1 1H NMR
;
(CDCl3) δ 1.40 (s, 9H), 2.55 (s br, 2H), 3.28 (s, 2H), 3.73 (s, 2H),
6.65 (s br, 1H), 7.30 (s, 5H), 8.60 (s br, 1H). Anal. Calcd for
C14H22N4O3: C, 57.14; H, 7.48; N, 19.05. Found: C, 57.06; H,
7.61; N, 18.91.
Boc-Nrh P h e-a za Leu -OMe (4e): yield 44%; mp 114 °C; IR
(Nujol) 3250, 1690 cm-1; 1H NMR (CDCl3) δ 0.92 (d, 6H, J ) 6.5
Hz), 1.35 (s, 9H), 1.9 (m, 1H), 3.33 (d, 2H, J ) 7.3 Hz), 3.47 (s,
2H), 3.67 (s, 3H), 3.95 (s, 2H), 5.79 (s br, 1H), 7.35 (m, 5H), 9.86
(s br, 1H); 13C NMR (CDCl3) δ 19.96 (q, J ) 125 Hz), 26.67 (d,
J ) 129 Hz), 28.13 (q, J ) 127 Hz), 53.26 (q, J ) 147 Hz), 56.93
(t, J ) 147 Hz), 59.35 (t, J ) 137 Hz), 63.31 (t, J ) 137 Hz),
80.92 (s), 128.09 (d, J ) 161 Hz), 128.53 (d, J ) 160 Hz), 129.55
(d, J ) 158 Hz), 135.16 (s), 156.17 (s), 156.56 (s), 168.68 (s); HR-
MS FAB m/z for C20H33N4O5 calcd 409.2451 (M + H+), obsd
409.2456. Anal. Calcd: C, 58.68; H, 8.07; N, 13.69. Found: C,
58.76; H, 8.10; N, 13.63.
Br CH2CO-a za Gly-OtBu (3, R1 ) H, R ) OtBu): yield 94%;
mp 77 °C; IR (KBr) 3500-3100, 1723, 1706, 1671 cm-1; 1H NMR
(CDCl3) δ 1.54 (s, 9H), 3.97 (s, 2H), 7.03 (s br, 1H), 8.75 (s br,
1H). Anal. Calcd for C7H13N2O3Br: C, 33.20; H, 5.14; N, 11.07;
Br, 31.62. Found: C, 33.07; H, 5.10; N, 10.78; Br, 31.44.
Br CH2CO-a za Gly-OBn (3, R1 ) H, R) OCH2Ph): yield 80%;
mp 98 °C; IR (Nujol) 3330, 3250, 1720, 1660 cm-1 1H NMR
;
Boc-Nrh Leu -a za Leu -OMe (4f): yield 42%; mp 93 °C; IR
(CDCl3) δ 3.90 (s, 2H), 5.19 (s, 2H), 6.88 (s br, 1H), 7.37 (m, 5H),
8.25 (s br, 1H). Anal. Calcd for C10H11N2O3Br: C, 41.81; H, 3.83;
N, 9.76; Br, 27.87. Found: C, 41.54; H, 3.91; N, 9.59; Br, 27.45.
Br CH2CO-a za Leu -OMe (3, R1 ) CH2CH(CH3)2, R ) OCH3):
1
(Nujol) 3206, 1711, 1672 cm-1; H NMR (CDCl3) δ 0.86 (d, J )
6.8 Hz, 6H), 0.92 (d, J ) 6.6 Hz, 6H), 1.37 (s, 9H), 1.65 (m, 1H),
1.82 (m, 1H), 2.47 (d, J ) 7.5 Hz, 2H), 3.27 (d, J ) 7 Hz, 2H),
3.38 (s, 2H), 3.62 (s, 3H), 5.52 (s br, 1H), 9.89 (s br, 1H); 13C
NMR (CDCl3) δ 20.30 (q, J ) 125 Hz), 20.90 (q, J ) 125 Hz),
26.88 (d, J ) 124 Hz), 27.07 (d, J ) 124 Hz), 28.58 (q, J ) 126.5
Hz), 53.57 (q, J ) 147 Hz), 57.40 (t, J ) 136 Hz), 62.06 (t, J )
133 Hz), 68.54 (t, J ) 130 Hz), 81.18 (s), 156.64 (s), 156.95 (s),
169.21 (s); HR-MS FAB m/z for C17H34N4O5 calcd 375.2607 (M
+ H+), obsd 375.2603. Anal. Calcd: C, 54.54; H, 9.10; N, 14.97.
Found: C, 54.32; H, 9.22; N, 15.15.
yield 99%; oil; IR (Nujol) 3250, 1650 cm-1 1H NMR (CDCl3) δ
;
0.93 (d, 6H, J ) 6.5 Hz), 1.9 (m, 1H), 3.35 (d, 2H, J ) 7.5 Hz),
3.75 (s, 3H), 3.88 (s, 2H), 7.09 (s br, 1H); 13C NMR (CDCl3) δ
19.9 (q, J ) 126 Hz), 26.4 (t, J ) 154 Hz), 26.9 (d, J ) 126 Hz),
53.6 (q, J ) 143 Hz), 56.8 (t, J ) 140 Hz), 155 (s), 163 (s). Anal.
Calcd for C8H15N2O3Br: C, 35.95; H, 5.62; N, 10.49; Br, 25.96.
Found: C, 35.96; H, 5.56; N, 10.47; Br, 25.87.
Br CH 2CO-Na za Leu -OMe (5, R1 ) CH2CH(CH3)2, R
)
Boc-Nrh Va l-a za Gly-OBn (4g): yield 72%; oil; IR (KBr)
3652-3121, 1748-1634 cm-1; 1H NMR (CDCl3)12 δ 0.96 (d, 6H,
J ) 6.1 Hz), 1.39 (s, 9H), 3 (m, 1H), 3.38 (s, 2H), 5.08 (s, 2H),
5.75 (s br, 1H), 6.55 (s br, 1H), 9.96 (s br, 1H). For elemental
analysis the hydrazinopeptoide 4g was deprotected.
OCH3): yield 80%; mp 108 °C; IR (Nujol) 3250, 1650 cm-1
;
1H
NMR (CDCl3)11 δ 0.93 (d, 6H, J ) 6.7 Hz), 1.95 (m, 1H), 3.41
(br, 2H), 3.79 (s, 3H), 3.89 (s, 2H), 8.55 (s br, 1H); 13C NMR
(CDCl3) δ 20.3 (q, J ) 126 Hz), 26.9 (d, J ) 154 Hz), 28.1 (t, J
) 131 Hz), 53.2 (q, J ) 148 Hz), 55.7 (t, J ) 140 Hz), 156.6 (s),
169.5 (s). Anal. Calcd for C8H15N2O3Br: C, 35.95; H, 5.62; N,
10.49; Br, 25.96. Found: C, 35.91; H, 5.52; N, 10.50; Br, 25.78.
Br CH2CO-Na za Leu -NH2 (5, R1 ) CH2CH(CH3)2, R ) NH2):
yield 54%; mp 168 °C; IR (KBr) 3367, 3191, 1712, 1665, 1623
Boc-Nrh Va l-NHNH2: yield 68%; mp 108 °C; IR (KBr) 3376,
1
3324, 3220, 3127, 1702, 1680, 1619 cm-1; H NMR (CDCl3)12
δ
1.14 (d, 6H, J ) 6.5 Hz), 1.53 (s, 9H), 3.15 (m, 1H), 3.48 (s, 2H),
3.93 (s br, 2H), 5.75 (s br, 1H), 9.46 (s br, 1H); 13C NMR (CDCl3)
δ 18.2 (q, J ) 125 Hz), 28.6 (q, J ) 126 Hz), 57.3 (d, J ) 135
Hz), 58.5 (t, J ) 141 Hz), 81.2 (s), 156.9 (s), 170.3 (s). Anal. Calcd
for C10H22N4O3: C, 48.78; H, 8.94; N, 22.77. Found: C, 48.80;
H, 8.69; N, 23.03.
cm-1 1H NMR (DMSO-d6) δ 0.85 (br, 6H), 1.88 (m, 1H), 2.82
;
(dd, 1H, J ) 10.5, 6.8 Hz), 3.69 (dd, 1H, J ) 10.5, 6.8 Hz), 3.91
(d, 1H, J ) 12.8 Hz), 4.21 (d, 1H, J ) 12.8 Hz), 6.21 (s, 2H),
8.58 (s, 1H). Anal. Calcd for C7H14N3O2Br: C, 33.33; H, 5.56; N,
16.67; Br, 31.75. Found: C, 33.34; H, 5.65; N, 16.92; Br, 31.44.
Step B. To a stirred solution of N-protected hydrazine (20
mmol, 3 equiv) in chloroform (12 mL) was added slowly the
R-bromo hydrazide 3 (10 mmol, 1 equiv) in chloroform (5 mL).
The reaction mixture was refluxed over a period of 12 h and,
after cooling, washed once with NaHCO3 1 N (30 mL) and twice
with water (30 mL). The organic phase was dried over Na2SO4.
The solvent was removed under reduced pressure, and the crude
product was purified by silica gel chromathography (hexane-
EtOAc as eluent 1:1).
Boc-Nrh Tyr (Bzl)-a za Gly-OBn (4h ): yield 94%; mp 60 °C;
IR (KBr) 3400-3100, 1750-1680, 1620 cm-1; 1H NMR (CDCl3)
δ 1.26 (s, 9H), 3.42 (s, 2H), 3.80 (s, 2H), 4.98 (s, 2H), 5.08 (s,
2H), 5.61 (s br, 1H), 6.40 (s br, 1H), 7.02 (AB, J ) 8.5 Hz, 4H),
7.22-7.40 (m, 5H), 9.70 (s br, 1H); HR-MS FAB m/z for
C
29H34N4O6 calcd 535.2557 (M + H+), obsd 535.2554. Anal.
Calcd: C, 65.17; H, 6.37; N, 10.48. Found: C, 65.00; H, 6.35; N,
10.24.
Boc-Nrh -h om oSer (Bzl)-a za Gly-OBn (4i): yield 53%; mp
1
90 °C; IR (KBr) 3277, 1747, 1698, 1674 cm-1; H NMR (CDCl3)
δ 1.64 (s, 9H), 3.3 (t br, 2H), 3.83 (s, 2H), 3.87 (t br, 2H), 4.74 (s,
2H), 5.36 (s, 2H), 6.83 (s br, 1H), 7.00 (s br, 1H), 7.55 (m, 10H),
10.1 (s br, 1H); HR-MS FAB m/z for C24H32N4O6 calcd 473.2400
(M + H+), obsd 473.2384. Anal. Calcd: C, 61.02; H, 6.78; N, 11.86.
Found: C, 60.76; H, 7.10; N, 11.92.
Nrh Ala -a za Gly-OtBu (4a ): yield 70%; mp 101 °C; IR (Nujol)
3340, 3310, 1730, 1705, 1680, 1650 cm-1 1H NMR (CDCl3) δ
;
1.45 (s, 9H), 2.50 (s, 3H), 3.00 (s br, 2H), 3.25 (s, 2H), 6.75 (s br,
1H), 8.40 (s br, 1H). Anal. Calcd for C8H18N4O3: C, 44.03; H,
8.26; N, 25.69. Found: C, 43.92; H, 8.03; N, 25.53.
(12) These values were obtained at 55 °C (78 °C for 7) as the room
temperature spectrum is poorly resolved because of partial coalescence
of most of the signals.
(11) Han, H. H.; J anda, K. D. J . Am. Chem. Soc. 1996, 118, 2339-
2344.